A number of conditions which afflict humans and other animals are attributable to disorders in metabolizing particular amino acids. In many of these conditions, treatment involves restricting the dietary intake of the particular amino acid or amino acids associated with the condition. However, therapies based on dietary restriction requires patient compliance and also requires that the patient know whether a particular food contains the particular amino acid or amino acids associated with the condition.
For example, phenylketonuria (“PKU”) is hyperaminoacidemia of phenylalanine (Phe) associated with an inborn error of phenylalanine metabolism, mutation of the gene encoding phenylalanine 4-hydroxylase (“PAH”), which converts phenylalanine to tyrosine. In some cases, an additional metabolic defect occurs in the synthetic pathway of either dihydropteridine or tetrahydrobiopterin (“BH4”), PAH co-factors, contributing further to the hyperphenylalaninemia (“HPA”). Whereas a normal plasma Phe level is approximately 0.05 mM (Pardridge, “Blood-Brain Barrier Amino Acid Transport: Clinical Implications,” chapter 6 in Inborn Errors of Metabolism in Humans, Cockburn et al., eds, Lancaster, England: MTP Press Ltd. (1980) (“Pardridge”)), untreated “classic” PKU patients have plasma Phe levels above 1 mM (e.g., plasma Phe levels of from about 1 mM to about 2.5 mM or more), and, although treatment with a low-Phe diet has a goal of reducing plasma Phe to below 0.3 mM, this is difficult to attain due to dietary compliance problems. In the US, 1 in 10,000 babies are born with PKU.
The excessive levels of plasma phenylalanine observed in PKU combined with the relatively high affinity of Phe for binding sites on carrier protein of the neutral amino acid transport system in the blood-brain barrier (“BBB”) leads to (i) accumulation of Phe and its neurotoxic metabolites (e.g., phenylpyruvate, phenylacetate, phenyllactate) in the brain and (ii) depressed levels of non-Phe neutral amino acids entering the brain, resulting in disturbed brain development and function, since key cerebral pathways of metabolism (e.g., synthesis of neurotransmitters) require precursor amino acids, such as tyrosine. This depression is pronounced for tyrosine, which is low in the plasma supply due to the PKU metabolic error in the enzyme responsible for converting phenylalanine to tyrosine. Current thought is that the neurological deficits of PKU are due predominantly to the depression of levels of non-Phe neutral amino acids entering the brain (Kaufman, “Some Facts Relevant to a Consideration of a Possible Alternative Treatment for Classical Phenylketonuria,” J. Inher. Metab. Dis., 21 (supplement 3):4-19 (1998) (“Kaufman”)).
Although a diet low in phenylalanine can reduce plasma Phe levels in “classic” PKU below 0.3 mM and ameliorate the mental retardation associated with untreated PKU, dietary compliance becomes problematic as PKU patients reach adolescence, leading to a rise in plasma Phe levels and to both loss in intelligence and white matter changes in the brain. Nutritional deficiencies can also result from Phe-restricted diets. Alternative treatments have thus been developed. For example, to overcome suspected depletion of the neurotransmitters dopamine and serotonin, PKU patients have been treated with the neurotransmitter precursors tyrosine and tryptophan (Lou, “Large Doses of Tryptophan and Tyrosine as Potential Therapeutic Alternative to Dietary Phenylalanine Restriction in Phenylketonuria,” Lancet, 2:150-151 (1983)). To reduce influx of Phe into the brain, a supplement of branched chain neutral amino acids containing valine, isoleucine, and leucine, was administered to older PKU patients (Berry et al, “Valine, Isoleucine and Leucine. A New Treatment for Phenylketonuria,” Am. J. Dis. Child., 144:539-543 (1990) (“Berry”)), who reported significant improvement in behavioral deficits. In Kaufman, it was proposed that the addition of the neurotransmitter precursors, tyrosine and tryptophan to Berry's supplement, should lead to further improvement. However, efficacy of these dietary amino acid supplement treatments has been controversial.
Tyrosinemia is another example of a condition that is attributable to a disorder in metabolizing particular amino acids. More particularly, tyrosinemia is a disorder caused by a defect in the terminal enzyme of the tyrosine metabolic pathway, leading to accumulation of fumarylacetoacetate, which converts to succinylacetone, which accumulates and is toxic to the liver. Tyrosinemia is associated with liver failure, liver diseases, and hepatocarcinoma. Liver transplantation can restore normal enzyme activity to the tyrosine metabolic pathway and is utilized in advanced cases. However this is a difficult and expensive therapy. Another currently employed therapy for tyrosinemia includes a two-fold approach: (i) use of a new inhibitor of tyrosine hydroxylase, NTBC ((2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione), which prevents formation of succinylacetone; and (ii) a diet low in both tyrosine and phenylalanine to manage the amount of tyrosine which must be metabolized. However, safety issues regarding NTBC are unanswered to date, and dietary restriction of tyrosine and phenylalanine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic, especially in adolescents and adults.
Alkaptonuria is another example of a condition that is attributable to a disorder in metabolizing particular amino acids. Current therapies include restricting dietary intake of phenylalanine and tyrosine to reduce accumulation of the metabolite, homogentisic acid. Some patients take NTBC and vitamin C to reduce homogentisic acid aggregates. However, safety issues regarding NTBC are unanswered to date, and dietary restriction of tyrosine and phenylalanine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic.
Homocystinuria is another example of a condition that is attributable to a disorder in metabolizing particular amino acids. Patients with this condition frequently follow a methionine restricted diet. However, dietary restriction of methionine is dependent on patient knowledge and compliance, which, as mentioned above, can be problematic.
A number of conditions are attributable to metabolic disorders affecting the metabolism of the branched chain amino acids (“BCAAs”), such as leucine, isoleucine, and valine. Leucine, isoleucine, and valine are essential amino acids which must be obtained from dietary protein. A defect in one step of a multistep metabolic pathway which converts the BCAAs to energy, results in accumulation of an intermediate metabolite of the BCAA to toxic levels, causing disease. This is a large group of diseases that includes, for example, maple syrup urine disease (“MSUD”), isovaleric acidemia, methylmalonic acidemia, and propionic acidemia. These diseases are treated with special dietary formulas low in the BCAA having the metabolic defect. However, as discussed above, successful management of such diseases and conditions by dietary restriction of a particular amino acid or a particular set of amino acids is dependent on patient knowledge and compliance, which can be problematic.
In view of the above, there is a need for methods and materials for treating conditions, such as phenylketonuria, that are attributable to a disorder in metabolizing particular amino acids, and the present invention, in part, is directed to meeting this need.